Cargando…

Fat‐Specific Protein 27 Regulation of Vascular Function in Human Obesity

BACKGROUND: Pathophysiological mechanisms that connect obesity to cardiovascular disease are incompletely understood. FSP27 (Fat‐specific protein 27) is a lipid droplet‐associated protein that regulates lipolysis and insulin sensitivity in adipocytes. We unexpectedly discovered extensive FSP27 expre...

Descripción completa

Detalles Bibliográficos
Autores principales: Karki, Shakun, Farb, Melissa G., Sharma, Vishva M., Jash, Sukanta, Zizza, Elaina J., Hess, Donald T., Carmine, Brian, Carter, Cullen O., Pernar, Luise I., Apovian, Caroline M., Puri, Vishwajeet, Gokce, Noyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585348/
https://www.ncbi.nlm.nih.gov/pubmed/31433737
http://dx.doi.org/10.1161/JAHA.118.011431
_version_ 1783428690871320576
author Karki, Shakun
Farb, Melissa G.
Sharma, Vishva M.
Jash, Sukanta
Zizza, Elaina J.
Hess, Donald T.
Carmine, Brian
Carter, Cullen O.
Pernar, Luise I.
Apovian, Caroline M.
Puri, Vishwajeet
Gokce, Noyan
author_facet Karki, Shakun
Farb, Melissa G.
Sharma, Vishva M.
Jash, Sukanta
Zizza, Elaina J.
Hess, Donald T.
Carmine, Brian
Carter, Cullen O.
Pernar, Luise I.
Apovian, Caroline M.
Puri, Vishwajeet
Gokce, Noyan
author_sort Karki, Shakun
collection PubMed
description BACKGROUND: Pathophysiological mechanisms that connect obesity to cardiovascular disease are incompletely understood. FSP27 (Fat‐specific protein 27) is a lipid droplet‐associated protein that regulates lipolysis and insulin sensitivity in adipocytes. We unexpectedly discovered extensive FSP27 expression in human endothelial cells that is downregulated in association with visceral obesity. We sought to examine the functional role of FSP27 in the control of vascular phenotype. METHODS AND RESULTS: We biopsied paired subcutaneous and visceral fat depots from 61 obese individuals (body mass index 44±8 kg/m(2), age 48±4 years) during planned bariatric surgery. We characterized depot‐specific FSP27 expression in relation to adipose tissue microvascular insulin resistance, endothelial function and angiogenesis, and examined differential effects of FSP27 modification on vascular function. We observed markedly reduced vasodilator and angiogenic capacity of microvessels isolated from the visceral compared with subcutaneous adipose depots. Recombinant FSP27 and/or adenoviral FSP27 overexpression in human tissue increased endothelial nitric oxide synthase phosphorylation and nitric oxide production, and rescued vasomotor and angiogenic dysfunction (P<0.05), while siRNA‐mediated FSP27 knockdown had opposite effects. Mechanistically, we observed that FSP27 interacts with vascular endothelial growth factor‐A and exerts robust regulatory control over its expression. Lastly, in a subset of subjects followed longitudinally for 12±3 months after their bariatric surgery, 30% weight loss improved metabolic parameters and increased angiogenic capacity that correlated positively with increased FSP27 expression (r=0.79, P<0.05). CONCLUSIONS: Our data strongly support a key role and functional significance of FSP27 as a critical endogenous modulator of human microvascular function that has not been previously described. FSP27 may serve as a previously unrecognized regulator of arteriolar vasomotor capacity and angiogenesis which are pivotal in the pathogenesis of cardiometabolic diseases linked to obesity.
format Online
Article
Text
id pubmed-6585348
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-65853482019-06-27 Fat‐Specific Protein 27 Regulation of Vascular Function in Human Obesity Karki, Shakun Farb, Melissa G. Sharma, Vishva M. Jash, Sukanta Zizza, Elaina J. Hess, Donald T. Carmine, Brian Carter, Cullen O. Pernar, Luise I. Apovian, Caroline M. Puri, Vishwajeet Gokce, Noyan J Am Heart Assoc Original Research BACKGROUND: Pathophysiological mechanisms that connect obesity to cardiovascular disease are incompletely understood. FSP27 (Fat‐specific protein 27) is a lipid droplet‐associated protein that regulates lipolysis and insulin sensitivity in adipocytes. We unexpectedly discovered extensive FSP27 expression in human endothelial cells that is downregulated in association with visceral obesity. We sought to examine the functional role of FSP27 in the control of vascular phenotype. METHODS AND RESULTS: We biopsied paired subcutaneous and visceral fat depots from 61 obese individuals (body mass index 44±8 kg/m(2), age 48±4 years) during planned bariatric surgery. We characterized depot‐specific FSP27 expression in relation to adipose tissue microvascular insulin resistance, endothelial function and angiogenesis, and examined differential effects of FSP27 modification on vascular function. We observed markedly reduced vasodilator and angiogenic capacity of microvessels isolated from the visceral compared with subcutaneous adipose depots. Recombinant FSP27 and/or adenoviral FSP27 overexpression in human tissue increased endothelial nitric oxide synthase phosphorylation and nitric oxide production, and rescued vasomotor and angiogenic dysfunction (P<0.05), while siRNA‐mediated FSP27 knockdown had opposite effects. Mechanistically, we observed that FSP27 interacts with vascular endothelial growth factor‐A and exerts robust regulatory control over its expression. Lastly, in a subset of subjects followed longitudinally for 12±3 months after their bariatric surgery, 30% weight loss improved metabolic parameters and increased angiogenic capacity that correlated positively with increased FSP27 expression (r=0.79, P<0.05). CONCLUSIONS: Our data strongly support a key role and functional significance of FSP27 as a critical endogenous modulator of human microvascular function that has not been previously described. FSP27 may serve as a previously unrecognized regulator of arteriolar vasomotor capacity and angiogenesis which are pivotal in the pathogenesis of cardiometabolic diseases linked to obesity. John Wiley and Sons Inc. 2019-06-01 /pmc/articles/PMC6585348/ /pubmed/31433737 http://dx.doi.org/10.1161/JAHA.118.011431 Text en © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research
Karki, Shakun
Farb, Melissa G.
Sharma, Vishva M.
Jash, Sukanta
Zizza, Elaina J.
Hess, Donald T.
Carmine, Brian
Carter, Cullen O.
Pernar, Luise I.
Apovian, Caroline M.
Puri, Vishwajeet
Gokce, Noyan
Fat‐Specific Protein 27 Regulation of Vascular Function in Human Obesity
title Fat‐Specific Protein 27 Regulation of Vascular Function in Human Obesity
title_full Fat‐Specific Protein 27 Regulation of Vascular Function in Human Obesity
title_fullStr Fat‐Specific Protein 27 Regulation of Vascular Function in Human Obesity
title_full_unstemmed Fat‐Specific Protein 27 Regulation of Vascular Function in Human Obesity
title_short Fat‐Specific Protein 27 Regulation of Vascular Function in Human Obesity
title_sort fat‐specific protein 27 regulation of vascular function in human obesity
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585348/
https://www.ncbi.nlm.nih.gov/pubmed/31433737
http://dx.doi.org/10.1161/JAHA.118.011431
work_keys_str_mv AT karkishakun fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT farbmelissag fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT sharmavishvam fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT jashsukanta fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT zizzaelainaj fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT hessdonaldt fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT carminebrian fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT carterculleno fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT pernarluisei fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT apoviancarolinem fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT purivishwajeet fatspecificprotein27regulationofvascularfunctioninhumanobesity
AT gokcenoyan fatspecificprotein27regulationofvascularfunctioninhumanobesity